5 6-diaryl-pyrazine-2-amide derivatives as cb1 antagonists

ABSTRACT

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, in which R 1  and R 2  independently represent: a C 1-6 alkyl group; an optionally substituted (amino)C 1-4 alkyl-group; an optionally substituted non-aromatic C 3-15 carbocyclic group; a (C 3-12 cycloalkyl)C 1-3 alkyl-group; a group —(CH 2 ) r (phenyl) s  in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by Z; naphthyl; anthracenyl; an optionally substituted saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulphur or an additional nitrogen; 1-adamantylmethyl; a group —(CH 2 ) t  Het in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted and Het represents an optionally substituted aromatic heterocycle; or R 1  represents H and R 2  is as defined above; or R 1  and R 2  together with the nitrogen atom to which they are attached represent a saturated optionally substituted 5 to 8 membered heterocyclic group as defined above; X is CO or SO 2 ; Y is absent or represents NH optionally substitututed by a C 1-3 alkyl group; R 3  and R 4  independently represent phenyl, thienyl or pyridyl substituted by Z; Z represents a C 1-3 alkyl group, a C 1-3 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C 1-3 alkylamino, mono or di C 1-3 alkylamido, C 1-3 alkylsulphonyl, C 1-3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C 1-3 alkyl carbamoyl, sulphamoyl and acetyl; and R 5  is H, a C 1-3 alkyl group, a C 1-3 alkoxymethyl group, trifluoromethyl, a hydroxyC 1-3 alkyl group, C 1-3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C 1-3 alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula —CONHNR a R b ; with the provisos; and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

FIELD OF INVENTION

The present invention relates to certain pyrazine carboxamide compoundsof formula I, to processes for preparing such compounds, to their use inthe treatment of obesity, psychiatric and neurological disorders, tomethods for their therapeutic use and to pharmaceutical compositionscontaining them.

BACKGROUND OF THE INVENTION

It is known that certain CB₁ modulators (known as antagonists or inverseagonists) are useful in the treatment of obesity, psychiatric andneurological disorders (WO01/70700 and EP 656354). However, there is aneed for CB₁ modulators with improved physicochemical properties and/orDMPK properties and/or pharmacodynamic properties.

Pyrazinecarboxamides are reported to possess antithrombotic properties(WO 92/02513). The compounds disclosed in this document are disclaimedfrom the compound claims of the present invention.5,6-Diphenyl-2-pyrazinecarboxylic acid is disclosed in CH 458 361.

DESCRIPTION OF THE INVENTION

The invention relates to compounds of the general formula (I)

and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof, in which

-   R¹ and R² independently represent:-   a C₁₋₆alkyl group;-   an (amino)C₁₋₄alkyl-group in which the amino is optionally    substituted by one or more C₁₋₃alkyl groups;-   an optionally substituted non-aromatic C₃₋₁₅carbocyclic group;-   a (C₃₋₁₂cycloalkyl)C₁₋₃alkyl-group;-   a group —(CH₂)_(r)(phenyl)_(s) in which r is 0, 1, 2, 3 or 4, s is 1    when r is 0 otherwise s is 1 or 2 and the phenyl groups are    optionally independently substituted by one, two or three groups    represented by Z;-   naphthyl;-   anthracenyl;-   a saturated 5 to 8 membered heterocyclic group containing one    nitrogen and optionally one of the following: oxygen, sulphur or an    additional nitrogen wherein the heterocyclic group is optionally    substituted by one or more C₁₋₃alkyl groups, hydroxy or benzyl;-   1-adamantylmethyl;-   a group —(CH₂)_(t) Het in which t is 0, 1, 2, 3 or 4, and the    alkylene chain is optionally substituted by one or more C₁₋₃alkyl    groups and Het represents an aromatic heterocycle optionally    substituted by one, two or three groups selected from a C₁₋₅alkyl    group, a C₁₋₅alkoxy group or halo;-   or R¹ represents H and R² is as defined above;-   or R¹ and R² together with the nitrogen atom to which they are    attached represent a saturated 5 to 8 membered heterocyclic group    containing one nitrogen and optionally one of the following: oxygen,    sulphur or an additional nitrogen; wherein the heterocyclic group is    optionally substituted by one or more C₁₋₃alkyl groups, hydroxy or    benzyl;-   X is CO or SO₂;-   Y is absent or represents NH optionally substitututed by a C₁₋₃alkyl    group;-   R³ and R⁴ independently represent phenyl, thienyl or pyridyl each of    which is optionally substituted by one, two or three groups    represented by Z;-   Z represents a C₁₋₃alkyl group, a C₁₋₃alkoxy group, hydroxy, halo,    trifluoromethyl, trifluoromethylthio, trifluoromethoxy,    trifluoromethylsulphonyl, nitro, amino, mono or di C₁₋₃alkylamino,    mono or di C₁₋₃alkylamido, C₁₋₃alkylsulphonyl, C₁₋₃alkoxycarbonyl,    carboxy, cyano, carbamoyl, mono or di C₁₋₃alkyl carbamoyl,    sulphamoyl and acetyl; and-   R⁵ is H, a C₁₋₃alkyl group, a C₁₋₃alkoxymethyl group,    trifluoromethyl, a hydroxyC₁₋₃alkyl group, C₁₋₃alkoxycarbonyl,    carboxy, cyano, carbamoyl, mono or di C₁₋₃alkylcarbamoyl, acetyl, or    hydrazinocarbonyl of formula —CONHNR^(a)R^(b) wherein R^(a) and    R^(b) are as previously defined for R¹ and R² respectively;-   with the proviso that when R¹ and R² together with the nitrogen atom    to which they are attached represent 4-methylpiperazin-1-yl or R¹    represents H and R² represents methyl or 1-benzylpiperidin-4-yl; X    is CO; Y is absent and R⁵ is H; then R³ and R⁴ do not both represent    4-methoxyphenyl.

Further values of R¹, R², R³, R⁴ and R⁵ in compounds of formula I nowfollow. It will be understood that such values may be used whereappropriate with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

In one group of compounds of formula I, R¹ represents H, R² representscyclohexyl, X is CO and Y is absent.

In a second group of compounds of formula I, R¹ and R² together with thenitrogen atom to which they are attached represent 1-piperidinyl.

In a third group of compounds of formula I, R¹ represents H and R²represents phenyl.

A fourth group of compounds of formula I is represented by formula Ia

and pharmaceutically acceptable salts, solvates and crystalline formsthereof, in which

-   R² represents cyclohexyl, 1-piperidinyl or phenyl;-   R⁶ represents H, chloro, bromo, methyl or methoxy; and-   when R⁷ represents H, R⁸ represents H or chloro; and-   when R⁷ represents chloro, R⁸ represents H or chloro.

In a fifth group of compounds of formula I R⁵ is H.

In a sixth group of compounds of formula I X is CO.

In a seventh group of compounds of formula I X is SO₂.

In an eighth group of compounds of formula I Y is absent.

“Pharmaceutically acceptable salt”, where such salts are possible,includes both pharmaceutically acceptable acid and base addition salts.A suitable pharmaceutically acceptable salt of a compound of Formula Iis, for example, an acid-addition salt of a compound of Formula I whichis sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example a salt of acompound of Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a sodium, calcium ormagnesium salt, or an ammonium salt,or a salt with an organic base suchas methylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof as well as mixtures in different proportions of theseparate enantiomers, where such isomers and enantiomers exist, as wellas pharmaceutically acceptable salts thereof and solvates thereof suchas for instance hydrates. Isomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Theenantiomers may be isolated by separation of racemate for example byfractional crystallisation, resolution or HPLC. The diastereomers may beisolated by separation of isomer mixtures for instance by fractionalcrystallisation, HPLC or flash chromatography. Alternatively thestereoisomers may be made by chiral synthesis from chiral startingmaterials under conditions which will not cause racemisation orepimerisation, or by derivatisation, with a chiral reagent. Allstereoisomers are included within the scope of the invention. Alltautomers, where possible, are included within the scope of theinvention.

The following definitions shall apply throughout the specification andthe appended claims.

Unless otherwise stated or indicated, the term “alkyl” denotes either astraight or branched alkyl group. Examples of said alkyl include methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl.Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and tertiarybutyl.

Unless otherwise stated or indicated, the term “alkoxy” denotes a groupO-alkyl, wherein alkyl is as defined above.

Unless otherwise stated or indicated, the term “halogen” shall meanfluorine, chlorine, bromine or iodine.

Specific compounds of the invention are one or more of the following:

-   N-(1-piperidinyl)-5,6-diphenyl-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-diphenyl-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;-   N-cyclohexyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;-   N,5,6-triphenyl-2-pyrazinecarboxamide;-   N-phenyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;-   N-phenyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;-   N-phenyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;-   N-phenyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;-   N-(1-piperidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-pyrazinecarboxamide;    and-   N-(1-piperidinyl)-6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-pyrazinecarboxamide;    and where applicable, optical isomers, tautomers, stereoisomers and    racemates thereof as well as pharmaceutically acceptable salts,    solvates and crystalline forms thereof.    Methods of Preparation

The compounds of the invention may be prepared as outlined belowaccording to any of the following methods. However, the invention is notlimited to these methods, the compounds may also be prepared asdescribed for structurally related compounds in the prior art.

Compounds of formula I in which X is CO may be prepared by reacting acompound of formula II

in which R³, R⁴ and R⁵ are as previously defined with an amine offormula IIIR¹R²YNH₂  IIIin an inert solvent, for example dichloromethane, in the presence of acoupling agent, for example a carbodimide, eg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and optionally in thepresence of a catalyst, for example a basic catalyst, eg4-dimethylamino-pyridine, at a temperature in the range of −25° C. to150° C.

Compounds of formula I in which X is SO₂ may be prepared by reacting acompound of formula IV

in which R³, R⁴ and R⁵ are as previously defined and A represents halowith an amine of formula IVR¹R²YNH₂  Vin an inert solvent, for example dichloromethane, and optionally in thepresence of a catalyst, for example a basic catalyst, eg4-dimethylamino-pyridine, at a temperature in the range of −25° C. to150° C.

Compounds of formulae II, III, IV and V may be prepared as described inthe Examples and by other methods known to those skilled in the art.Certain compounds of formulae II, III, IV and V are novel and areclaimed as a further aspect of the present invention as usefulintermediates. Specifically claimed are compounds of formula II in whichR³, R⁴ and R⁵ are as previously defined with the exception of5,6-diphenyl-2-pyrazinecarboxylic acid and5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxylic acid.

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

Persons skilled in the art will appreciate that, in order to obtaincompounds of the invention in an alternative and in some occasions, moreconvenient manner, the individual process steps mentioned hereinbeforemay be performed in different order, and/or the individual reactions maybe performed at different stage in the overall route (i.e. chemicaltransformations may be performed upon different intermediates to thoseassociated hereinbefore with a particular reaction).

The expression “inert solvent” refers to a solvent which does not reactwith the starting materials, reagents, intermediates or products in amanner which adversely affects the yield of the desired product.

Pharmaceutical Preparations

The compounds of the invention will normally be administered via theoral, parenteral, intravenous, intramuscular, subcutaneous or in otherinjectable ways, buccal, rectal, vaginal, transdermal and/or nasal routeand/or via inhalation, in the form of pharmaceutical preparationscomprising the active ingredient or a pharmaceutically acceptableaddition salt, in a pharmaceutically acceptable dosage form. Dependingupon the disorder and patient to be treated and the route ofadministration, the compositions may be administered at varying doses.

Suitable daily doses of the compounds of the invention in thetherapeutic treatment of humans are about 0.001-10 mg/kg body weight,preferably 0.01-1 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules whichmay be formulated by methods known to those skilled in the art toprovide doses of the active compound in the range of 0.5 mg to 500 mgfor example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.

A compound of the invention may also be combined with other anti-obesityagents such as Orlistat or a monoamine reuptake inhibitor, for exampleSibutramine. Furthermore, a compound of the invention may also becombined with therapeutic agents that are useful in the treatment ofdisorders or conditions associated with obesity (such as type IIdiabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance,hypertension, coronary heart disease, non-alcoholic steatorheichepatitis, osteoarthritis and some cancers) and psychiatric andneurological conditions.

According to a further aspect of the invention there is also provided apharmaceutical formulation including any of the compounds of theinvention, or pharmaceutically acceptable derivatives thereof, inadmixture with pharmaceutically acceptable adjuvants, diluents and/orcarriers.

Pharmacological Properties

The compounds of formula (I) are useful for the treatment of obesity,psychiatric disorders such as psychotic disorders, schizophrenia,bipolar disorders, anxiety, anxio-depressive disorders, depression,cognitive disorders, memory disorders, obsessive-compulsive disorders,anorexia, bulimia, attention disorders like ADHD, epilepsy, and relatedconditions, and neurological disorders such as dementia, neurologicaldisorders (e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson'sdisease, Huntington's chorea and Alzheimer's disease. The compounds arealso potentially useful for the treatment of immune, cardiovascular,reproductive and endocrine disorders, septic shock and diseases relatedto the respiratory and gastrointestinal systems (e.g. diarrhea). Thecompounds are also potentially useful as agents in treatment of extendedabuse, addiction and/or relapse indications, e.g. treating drug(nicotine, ethanol, cocaine, opiates, etc) dependence and/or treatingdrug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms. Thecompounds may also eliminate the increase in weight which normallyaccompanies the cessation of smoking.

In another aspect the present invention provides a compound of formula Ias previously defined for use as a medicament.

In a further aspect the present invention provides the use of a compoundof formula I (including the compounds of the proviso) in the preparationof a medicament for the treatment or prophylaxis of obesity, psychiatricdisorders such as psychotic disorders, schizophrenia, bipolar disorders,anxiety, anxio-depressive disorders, depression, cognitive disorders,memory disorders, obsessive-compulsive disorders, anorexia, bulimia,attention disorders like ADHD, epilepsy, and related conditions,neurological disorders such as dementia, neurological disorders (e.g.Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea andAlzheimer's Disease, immune, cardiovascular, reproductive and endocrinedisorders, septic shock, diseases related to the respiratory andgastrointestinal systems (e.g. diarrhea), and extended abuse, addictionand/or relapse indications, e.g. treating drug (nicotine, ethanol,cocaine, opiates, etc) dependence and/or treating drug (nicotine,ethanol, cocaine, opiates, etc) withdrawal symptoms.

In a still further aspect the present invention provides a method oftreating obesity, psychiatric disorders such as psychotic disorders suchas schizophrenia and bipolar disorders, anxiety, anxio-depressivedisorders, depression, cognitive disorders, memory disorders,obsessive-compulsive disorders, anorexia, bulimia, attention disorderslike ADHD, epilepsy, and related conditions, neurological disorders suchas dementia, neurological disorders (e.g. Multiple Sclerosis),Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease,immune, cardiovascular, reproductive and endocrine disorders, septicshock, diseases related to the respiratory and gastrointestinal systems(e.g. diarrhea), and extended abuse, addiction and/or relapseindications, e.g. treating drug (nicotine, ethanol, cocaine, opiates,etc) dependence and/or treating drug (nicotine, ethanol, cocaine,opiates, etc) withdrawal symptoms comprising administering apharmacologically effective amount of a compound of formula I

and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof, in which

-   R¹ and R² independently represent:-   a C₁₋₆alkyl group;-   an (amino)C₁₋₄alkyl-group in which the amino is optionally    substituted by one or more C₁₋₃alkyl groups;-   an optionally substituted non-aromatic C₃₋₁₅carbocyclic group;-   a (C₃₋₁₂cycloalkyl)C₁₋₃alkyl-group;-   a group —(CH₂)_(r)(phenyl)_(s) in which r is 0, 1, 2, 3 or 4, s is 1    when r is 0 otherwise s is 1 or 2 and the phenyl groups are    optionally independently substituted by one, two or three groups    represented by Z;-   naphthyl;-   anthracenyl;-   a saturated 5 to 8 membered heterocyclic group containing one    nitrogen and optionally one of the following: oxygen, sulphur or an    additional nitrogen wherein the heterocyclic group is optionally    substituted by one or more C₁₋₃alkyl groups, hydroxy or benzyl;-   1-adamantylmethyl;-   a group —(CH₂)_(t) Het in which t is 0, 1, 2, 3 or 4, and the    alkylene chain is optionally substituted by one or more C₁₋₃alkyl    groups and Het represents an aromatic heterocycle optionally    substituted by one, two or three groups selected from a C₁₋₅alkyl    group, a C₁₋₅alkoxy group or halo;-   or R¹ represents H and R² is as defined above;-   or R¹ and R² together with the nitrogen atom to which they are    attached represent a saturated 5 to 8 membered heterocyclic group    containing one nitrogen and optionally one of the following: oxygen,    sulphur or an additional nitrogen; wherein the heterocyclic group is    optionally substituted by one or more C₁₋₃alkyl groups, hydroxy or    benzyl;-   X is CO or SO₂;-   Y is absent or represents NH optionally substitututed by a C₁₋₃alkyl    group;-   R³ and R⁴ independently represent phenyl, thienyl or pyridyl each of    which is optionally substituted by one, two or three groups    represented by Z;-   Z represents a C₁₋₃alkyl group, a C₁₋₃alkoxy group, hydroxy, halo,    trifluoromethyl, trifluoromethylthio, trifluoromethoxy,    trifluoromethylsulphonyl, nitro, amino, mono or di C₁₋₃alkylamino,    mono or di C₁₋₃alkylamido, C₁₋₃alkylsulphonyl, C₁₋₃alkoxycarbonyl,    carboxy, cyano, carbamoyl, mono or di C₁₋₃alkyl carbamoyl,    sulphamoyl and acetyl; and-   R⁵ is H, a C₁₋₃alkyl group, a C₁₋₃alkoxymethyl group,    trifluoromethyl, a hydroxyC₁₋₃alkyl group, C₁₋₃alkoxycarbonyl,    carboxy, cyano, carbamoyl, mono or di C₁₋₃alkylcarbamoyl, acetyl, or    hydrazinocarbonyl of formula —CONHNR^(a)R^(b) wherein R^(a) and    R^(b) are as previously defined for R¹ and R² respectively;    to a patient in need thereof.

The compounds of the present invention are particulary suitable for thetreatment of obesity, e.g. by reduction of appetite and body weight,maintenance of weight reduction and prevention of rebound.

EXAMPLES Abbreviations

-   DCM—dichloromethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   TEA—triethylamine-   TFA—trifluoroacetic acid-   DMSO—dimethyl sulfoxide-   DEA—Diethylamine-   PCC—Pyridinium chlorochromate

DCM—Dichloromethane t triplet s singlet d doublet q quartet qvintquintet m multiplet br broad bs broad singlet dm doublet of multiplet btbroad triplet dd doublet of doubletGeneral Experimental Procedures

Mass spectra were recorded on either a Micromass ZQ single quadrupole ora Micromass LCZ single quadrupole mass spectrometer both equipped with apneumatically assisted electrospray interface (LC-MS). ¹H NMRmeasurements were performed on either a Varian Mercury 300 or a VarianInova 500, operating at ¹H frequencies of 300 and 500 MHz respectively.Chemical shifts are given in ppm with CDCl₃ as internal standard.

Purification was performed on a semipreparative HPLC with a masstriggered fraction collector, Shimadzu QP 8000 single quadrupole massspectrometer equipped with 19×100 mm C8 column. The mobile phase usedwas, if nothing else is stated, acetonitrile and buffer (0.1 MNH₄Ac:acetonitrile 95:5).

For isolation of isomers, a Kromasil CN E9344 (250×20 mm i.d.) columnwas used. Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1ml/min). Fraction collection was guided using a UV-detector (330 nm).

Synthesis of Intermediates

The following intermediates were not commercially available andtherefore prepared as described in Preparation A, (Chem. Ber., 100,1967, p. 555).

Preparation A

(a) 5,6-diphenyl-pyrazine-2-carboxylic acid

The monohydrochloride of 2,3-diaminopropionic acid (500 mg, 3.56 mmol)and benzil (890 mg, 4.23 mmol) were added to a solution of sodiumhydroxide (677 mg, 16.93 mmol) in methanol (10 ml). An extra portion ofmethanol was added (5 ml) and the reaction mixture was refluxed for 20minutes. The mixture was cooled to 25° C. and air was bubbled throughfor 30 minutes. Hydrochloric acid (aq, 2 M) was added until the reactionmixture reached pH 2. The solution was extracted with diethyl ether. Thecombined diethyl ether phases were dried (MgSO₄), filtrated andevaporated under reduced pressure to give the crude product. MS m/z 277(M+H)⁺. The crude product was used in steps described below withoutfurther purification.

(b) 5,6-Bis-(4-bromophenyl)-pyrazine-2-carboxylic acid

The title compound was prepared essentially as described in PreparationA step (a), using monohydrochloride of 2,3-diaminopropionic acid (600mg, 4.26 mmol) and 4,4′-dibromobenzil (1.745 g, 4.26 mmol, 90%) asstarting materials. The reaction mixture was refluxed for 2 hours andair was bubbled through for 1 hour. Hydrochloric acid (aq, 2 M) wasadded until pH 2. The mixture was evaporated under reduced pressure andthe residue was dissolved in water. The solution was extracted withdiethyl ether, the combined diethyl ether phases were dried (MgSO₄),filtered and evaporated under reduced pressure. The crude product (500mg, 27%) was used in steps described below without further purification.MS m/z 435, 437, 439 (M+H)⁺.

(c) 5,6-Di-p-tolyl-pyrazine-2-carboxylic acid

The title compound was prepared as described in Preparation A step (a)using 4,4′-dimethylbenzil (848 mg, 3.56 mmol). The reaction mixture washowever refluxed for 1 hour and air was bubbled through the reactionmixture for about 7 hours. The mixture was evaporated and the residuewas dissolved in water. Hydrochloric acid (aq, 2 M) was added until pH 2was reached. The solution was extracted with diethyl ether. The combineddiethyl ether phases were dried (MgSO₄), filtered and evaporated underreduced pressure. The crude product (918 mg, 85%) was used in stepsdescribed below without further purification. MS m/z 305 (M+H)⁺.

(d) 5,6-Bis-(4-methoxyphenyl)pyrazine-2-carboxylic acid

The title compound was prepared as described in Preparation A step (c)using 4,4′-dimethoxybenzil (961 mg, 3,56 mmol) as starting material. Thereaction mixture was refluxed over night and air was bubbled through themixture for 8 hours. The crude product (435 mg, 36%) was used in stepsdescribed below without further purification. MS m/z 335 (M+H)⁺.

(e) 5,6-Bis-(4-chlorophenyl)pyrazine-2-carboxylic acid

The title compound was prepared as described in Preparation A step (c)using 4,4′-dichlorobenzil (993 mg, 3.56 mmol). Reflux for 1 hour gavedirectly the crude product (923 mg, 75%) that was used in stepsdescribed below without further purification. MS m/z 343, 345, 347(M−H)⁻.

(f) 5,6-Bis-(2-chlorophenyl)pyrazine-2-carboxylic acid

The title compound was prepared as described in Preparation A step (c)using 2,2′-dichlorobenzil (993 mg, 3.56 mmol). The crude product (895mg, 73%) was used in steps described below without further purification.MS m/z 343, 345, 347 (M−H)⁻.

(h) 1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)ethane-1,2-dione

2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.7 g, 9.01 mmol) wasdissolved in 1,2-dichloroethane (25 ml) and freshly made PCC (3.89 g,18.02 mmol), pyridine (1.43 g, 18.02 mmol) and molecular sieves wereadded. The reaction mixture was refluxed under inert atmosphereovernight. The solution was cooled to 25° C., filtered through Silicaand then solvent was evaporated under reduced pressure. The crudeproduct (1.9 g, 66%) was used directly in the next step. ¹H NMR (500MHz) δ 7.97 (d, 2H), 7.84 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.44 (d,1H).

(i) 5-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)pyrazine-2-carboxylic acidand 6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrazine-2-carboxylic acid

The title compounds were prepared as described in Preparation A step(a), using 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)ethane-1,2-dione(1.85 g; 5.90 mmol) from Preparation A step (g) and the monochloride of2,3-diaminopropionic acid (0.61 g, 5.90 mmol) as starting materials. Themixture was refluxed for 30 minutes and then directly worked-up. Thecrude product was allowed to stand over night to aromatise. Flashchromatography (SiO₂, DCM:methanol 10:1, 1% Acetic acid) gave the isomermixture (0.2 g, 10%). MS m/z 377, 379, 381 (M−H)⁻.

EXAMPLES OF THE INVENTION Example 1N-(1-piperidinyl)-5,6-diphenyl-2-pyrazinecarboxamide

5,6-Diphenyl-pyrazine-2-carboxylic acid (500 mg, 1.81 mmol) fromPreparation A, step (a), was dissolved in DCM (4 ml) and DMF (150 μl).DMAP (22 mg, 0.18 mmol) and 1-aminopiperidine (218 mg, 2.17 mmol) wereadded and the solution was cooled to 0° C. A slurry of EDC (1.99 mmol,in 2 mL DCM and 100 μl DMF) was added dropwise. The reaction mixture wasstirred at 25° C. After 17 hours additional 1-aminopiperidine (40 mg,0.40 mmol) and EDC (76 mg, 0.40 mmol) was added, and the mixture wasstirred for an additional 3 hours. The crude was diluted with DCM (5 ml)and washed with a saturated solution of NaHCO₃. The organic phase wasdried (MgSO₄), filtered and evaporated. Flash chromatography (SiO₂,ethyl acetate:hexane 2:1) gave the subtitle compound (160 mg, 25%) as awhite solid.

¹H NMR (300 MHz) δ 9.41 (s, 1H), 8.52 (s, 1H), 7.50-7.29 (m, 10H), 2.94(t, 4H), 1.81 (m, 4H), 1.50 (m, 2H).

MS m/z 359 (M+H)⁺.

Example 2 N-(1-piperidinyl)-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide

To 5,6-Bis-(4-bromophenyl)-pyrazine-2-carboxylic acid (108 mg, 0.25mmol) from Preparation A, step (b), DMAP (0.025 mmol, in 500 μl DCM),1-aminopiperidine (0.25 mmol, in 1100 μl DCM), EDC (0.27 mmol, in 1100μl DCM and cooled to 8° C.) were added. The reaction mixture was stirredat 25° C. for 20 h, then washed with saturated NaHCO₃ solution, dried(MgSO₄), filtered and evaporated. Semipreparatory HPLC (0.01% TEA in thebuffered phase) gave the subtitle compound (6.7 mg, 5.4%).

¹H NMR (300 MHz) δ 9.41 (s, 1H), 8.48 (s, 1H), 7.54 (d, 2H), 7.51 (d,2H), 7.36 (d, 2H), 7.34 (d, 2H), 2.94 (t, 4H), 1.81 (m, 4H), 1.55-1.45(m, 2H).

MS m/z 515, 517, 519 (M+H)⁺.

Example 3N-(1-piperidinyl)-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide

5,6-Di-p-tolyl-pyrazine-2-carboxylic acid (76 mg, 0.25 mmol) fromPreparation A, step (c), was used as described in Example 2 to give thetitle compound (27 mg, 28%).

¹H NMR (300 MHz) δ 9.35 (s, 1H), 8.57 (s, 1H), 7.38 (d, 4H), 7.18 (d,2H), 7.13 (d, 2H), 2.92 (t, 4H), 2.40 (s, 3H), 2.37 (s, 3H), 1.86-1.75(m, 4H), 1.54-1.44 (m, 2H).

MS m/z 387 (M+H)⁺.

Example 4N-(1-piperidinyl)-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-methoxyphenyl)-pyrazine-2-carboxylic acid (84 mg, 0.25 mmol)from Preparation A, step (d), was used as described Example 2 to givethe title compound (20 mg, 19%).

¹H NMR (300 MHz) δ 9.31 (s, 1H), 8.57 (s, 1H), 7.46 (d, 2H), 7.44 (d,2H), 6.90 (d, 2H), 6.86 (d, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.93 (t,4H), 1.80 (m, 4H), 1.54-1.45 (m, 2H).

MS m/z 419 (M+H)⁺.

Example 5N-(1-piperidinyl)-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-chlorophenyl)-pyrazine-2-carboxylic acid (86 mg, 0.25 mmol)from Preparation A, step (e), was used as described in Example 2 to givethe subtitle compound (16 mg, 15%).

¹H NMR (300 MHz) δ 9.40 (s, 1H), 8.49 (s, 1H), 7.45-7.31 (m, 8H), 2.94(t, 4H), 1.80 (m, 4H), 1.54-1.45 (m, 2H).

MS m/z 427, 429, 431 (M+H)⁺.

Example 6N-(1-piperidinyl)-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(2-chlorophenyl)-pyrazine-2-carboxylic acid (86 mg, 0.25 mmol)from Preparation A, step (f), was used as described in Example 2 to givethe subtitle compound (6 mg, 6%).

¹H NMR (300 MHz) δ 9.52 (s, 1H), 8.52 (s, 1H), 7.44-7.17 (d, 8H),2.94-2.88 (t, 4H), 1.85-1.70 (m, 4H), 1.52-1.44 (m, 2H).

MS m/z 427, 429, 431 (M+H)⁺.

Example 7 N-cyclohexyl-5,6-diphenyl-2-pyrazinecarboxamide

5,6-diphenyl-pyrazine-2-carboxylic acid (70 mg, 0.25 mmol) fromPreparation A, step (a), was reacted essentially as described in Example2 but with cyclohexylamine (0.25 mmol, in 1 ml DCM), DMAP (0.025 mmol,in 0.5 ml DCM), EDC (0.28 mmol, in 1 ml DCM, and cooled to 8° C.) andDMF (100 μl). Semipreparatory HPLC (0.15% TFA/water:acetonitrile 95:5instead of the buffer phase) gave the title compound (7 mg, 8%) afterwashing with Na₂CO₃ solution.

¹H NMR (300 MHz) δ 9.41 (s, 1H), 7.78 (d, 1H), 7.49-7.28 (m, 10H),4.12-3.97 (m, 1H), 2.13-1.23 (m, 10H).

MS m/z 358 (M+H)⁺.

Example 8 N-cyclohexyl-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-bromophenyl)-pyrazine-2-carboxylic acid (109 mg, 0.25 mmol)from Preparation A, step (b), was used as described in Example 7.Semipreparatory HPLC (0.15% TFA/water:acetonitrile 95:5 instead of thebuffer phase) gave the title compound (7 mg, 8%) after washing withNa₂CO₃ solution.

¹H NMR (300 MHz) δ 9.41 (s, 1H), 7.68 (s, 1H), 7.54 (d, 2H), 7.50 (d,2H), 7.36 (d, 2H), 7.34 (d, 2H), 4.11-3.96 (m, 1H), 2.12-1.20 (m, 10H).

MS m/z 514, 516, 518 (M+H)⁺.

Example 9 N-cyclohexyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide

5,6-Di-p-tolyl-pyrazine-2-carboxylic acid (76 mg, 0.25 mmol) fromPreparation A, step (c), was used as described in Example 7.Semipreparatory HPLC (0.01% TEA in the buffer phase) gave the subtitlecompound (4 mg, 4%).

¹H NMR (300 MHz) δ 9.36 (s, 1H), 7.77 (d, 1H), 7.39 (d, 4H), 7.18 (d,2H), 7.13 (d, 2H), 4.10-3.96 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H),2.09-1.20 (m, 10H).

MS m/z 386 (M+H)⁺.

Example 10 N-cyclohexyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide

5,6-Bis(4-methoxyphenyl)-pyrazine-2-carboxylic acid (76 mg, 0.25 mmol)from Preparation A, step (d), was used essentially as described inExample 7 but the reaction mixture was first stirred overnight, thenmore cyclohexylamine (25 mg, 0.25 mmol) was added and the mixture wasstirred for an additional two days prior to workup. Semipreparatory HPLC(0.15% TFA in the buffered phase) gave the title compound (12 mg, 11%).

¹H NMR (300 MHz) δ 9.32 (s, 1H), 7.76 (d, 1H), 7.47 (d, 2H), 7.45 (d,2H), 6.90 (d, 2H), 6.86 (d, 2H), 4.10-3.96 (m, 1H), 3.86 (s, 3H), 3.84(s, 3H), 2.09-1.17 (m, 10H).

MS m/z 418 (M+H)⁺.

Example 11 N-cyclohexyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-chlorophenyl)pyrazine-2-carboxylic acid (86 mg, 0.25 mmol)from Preparation A, step (e), was used as described in Example 10 togive the title compound (7 mg, 8%) after washing with Na₂CO₃ solution.

¹H NMR (300 MHz) δ 9.41 (s, 1H), 7.69 (s, 1H), 7.47-7.30 (m, 8H),4.10-3.97 (m, 1H), 2.10-1.18 (m, 10H).

MS m/z 426, 428, 430 (M+H)⁺.

Example 12 N-cyclohexyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(2-chlorophenyl)-pyrazine-2-carboxylic acid (86 mg, 0.25 mmol)from preparation A step (f) was used as described in Example 10, to givethe title compound (14 mg, 13%).

¹H NMR (300 MHz) δ 9.51 (s, 1H), 7.74 (s, 1H), 7.41-7.18 (m, 8H),4.10-3.97 (m, 1H), 2.07-1.14 (m, 10H).

MS m/z 426, 428, 430 (M+H)⁺.

Example 13 N,5,6-triphenyl-2-pyrazinecarboxamide

To 5,6-Diphenyl-pyrazine-2-carboxylic acid (70 mg, 0.25 mmol) fromPreparation A, step (a), DMAP (0.025 mmol, in 0.5 ml DCM), aniline (0.25mmol, in 1 ml DCM), EDC (0.28 mmol, in 1 ml DCM, cooled to 8° C.) andDMF (100 μl) were added. The reaction mixture was stirred at 25° C. overnight, then worked up as described in Example 2. Semipreparatory HPLC(0.15% TFA/water:acetonitrile 95:5 instead of the buffer phase) gave thetitle compound (27 mg, 30%) after washing with Na₂CO₃ solution.

¹H NMR (300 MHz) δ 9.75 (s, 1H), 9.52 (d, 1H), 7.80 (d, 2H), 7.55-7.32(m, 12H), 7.20 (t, 1H).

MS m/z 352 (M+H)⁺.

Example 14 N-phenyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide

5,6-Di-p-tolyl-pyrazine-2-carboxylic acid (77 mg, 0.25 mmol) fromPreparation A, step (c), was used as described in Example 13 to give thesubtitle compound (28 mg, 29%).

¹H NMR (500 MHz) δ 9.78 (s, 1H), 9.49 (s, 1H), 7.81 (d, 2H), 7.47-7.43(m, 6H), 7.25-7.17 (m, 5H), 2.45 (s, 3H), 2.41 (s, 3H).

MS m/z 380 (M+H)⁺.

Example 15 N-phenyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-methoxyphenyl)-pyrazine-2-carboxylic acid (85 mg, 0.25 mmol)from Preparation A step (d), was used as described in Example 13, togive the title compound (33 mg, 32%).

¹H NMR (300 MHz) δ 9.74 (s, 1H), 9.42 (s, 1H), 7.79 (d, 2H), 7.50 (d,4H), 7.42 (t, 2H), 7.19 (t, 1H), 6.94 (d, 2H), 6.89 (d, 2H), 3.88 (s,3H), 3.85 (s, 3H).

MS m/z 412 (M+H)⁺.

Example 16 N-phenyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(4-chlorophenyl)-pyrazine-2-carboxylic acid (87 mg, 0.25 mmol)from Preparation A, step (e), was used as described in Example 13, togive the subtitle compound (6 mg, 6%).

¹H NMR (300 MHz) δ 9.66 (s, 1H), 9.52 (s, 1H), 7.79 (d, 2H), 7.48-7.35(m, 10H), 7.21 (t, 1H).

MS m/z 420, 422, 424 (M+H)⁺.

Example 17 N-phenyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide

5,6-Bis-(2-chloro-phenyl)-pyrazine-2-carboxylic acid (87 mg, 0.25 mmol)from Preparation A, step (f), was treated as described in Example 13, togive the title compound (27 mg, 25%).

¹H NMR (500 MHz) δ 9.73 (s, 1H), 9.66 (s, 1H), 7.81(d, 2H), 7.46-7.22(m, 11H).

MS m/z 420, 422, 424 (M+H)⁺.

Example 185-(4-Chlorophenyl)-6-(2,4-dichlorophenyl)pyrazine-2-carboxylic acidpiperidin-1-ylamide and6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrazine-2-carboxylic acidpiperidin-1-ylamide

The mixture of5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrazine-2-carboxylic acid and6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrazine-2-carboxylic acid (78mg, 0.205 mmol) from Preparation A step (i) and thionyl chloride (147mg, 1.23 mmol) were refluxed in toluene (2 ml) for 3 hours. The solventand reagents were evaporated under reduced pressure and theintermediates were dissolved in DCM (1 ml). TEA (42 mg, 0.41 mmol) and1-aminopiperidine (21 mg, 0.205 mmol) were dissolved in DCM (1 ml) andadded. The reaction mixture was stirred at 25° C. overnight and thenevaporated under reduced pressure. Flash chromatography (SiO₂,heptane:ethyl acetate 1:1) gave a mixture of the title compounds (45 mg,47%, ratio of isomers 0.5:1). ¹H NMR (300 MHz) δ 9.46 (s, 1H), 8.39 (s,1H), 7.47-7.28 (m, 7H), 3.02-2.84 (m, 4H), 1.89-1.73 (m, 4H), 1.57-1.41(m, 2H) and 9.42 (s, 1H), 8.51 (s, 1H), 7.47-7.28 (m, 7H), 3.02-2.84 (m,4H), 1.89-1.73 (m, 4H), 1.57-1.41 (m, 2H).

Example 18(a)N-(1-piperidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-pyrazinecarboxamide

The title compound was isolated from the mixture prepared in Example 18(35 mg) by preparative chromatography (9 mg, 26%). ¹H NMR (300 MHz) δ9.46 (s, 1H), 8.38 (s, 1H), 7.46-7.24 (m, 7H), 2.89 (t, 4H), 1.78 (p,4H), 1.52-1.40 (m, 2H).

Example 18(b)N-(1-piperidinyl)-6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-pyrazinecarboxamide

The title compound was isolated from the mixture prepared in Example 18(35 mg) by preparative chromatography (11 mg, 31%). ¹H NMR (300 MHz) δ9.42 (s, 1H), 8.50 (s, 1H), 7.39-7.30 (m, 7H), 2.93 (t, 4H), 1.80 (p,4H), 1.54-1.43 (m, 2H).

Pharmacological Activity

Compounds of the present invention are active against the receptorproduct of the CB1 gene. The affinity of the compounds of the inventionfor central cannabinoid receptors is demonstrable in methods describedin Devane et al, Molecular Pharmacology, 1988, 34,605 or those describedin WO01/70700 or EP 656354. Alternatively the assay may be performed asfollows.

10 μg of membranes prepared from cells stably transfected with the CB1gene were suspended in 200 μl of 100 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, 50mM HEPES (pH 7.4), 1 mM DTT, 0.1% BSA and 100 μM GDP. To this was addedan EC80 concentration of agonist (CP55940), the required concentrationof test compound and 0.1 μCi [³⁵S]-GTPγS. The reaction was allowed toproceed at 30° C. for 45 min. Samples were then transferred on to GF/Bfilters using a cell harvester and washed with wash buffer (50 mM Tris(pH 7.4), 5 mM MgCl₂, 50 mM NaCl). Filters were then covered withscintilant and counted for the amount of [³⁵S]-GTPγS retained by thefilter.

Activity is measured in the absence of all ligands (minimum activity) orin the presence of an EC80 concentration of CP55940 (maximum activity).These activities are set as 0% and 100% activity respectively. Atvarious concentrations of novel ligand, activity is calculated as apercentage of the maximum activity and plotted. The data are fittedusing the equation y=A+((B−A)/1+((C/x)UD)) and the IC50 value determinedas the concentration required to give half maximal inhibition of GTTγSbinding under the conditions used.

The compounds of the present invention are active at the CB1 receptor(IC50<1 micromolar). Most preferred compounds have IC50<200 nanomolar.

1. A compound of formula (I)

and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof, in which R¹ and R² independently represent: aC₁₋₆alkyl group; an (amino)C₁₋₄alkyl-group in which the amino isoptionally substituted by one or more C₁₋₃alkyl groups; an optionallysubstituted non-aromatic C₃₋₁₅carbocyclic group; a(C₃₋₁₂cycloalkyl)C₁₋₃alkyl-group; a group —(CH₂)_(r)(phenyl)_(s) inwhich r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 andthe phenyl groups are optionally independently substituted by one, twoor three groups represented by Z; naphthyl; anthracenyl; a saturated 5to 8 membered heterocyclic group containing one nitrogen and optionallyone of the following: oxygen, sulphur or an additional nitrogen whereinthe heterocyclic group is optionally substituted by one or moreC₁₋₃alkyl groups, hydroxy or benzyl; 1-adamantylmethyl; a group—(CH₂)_(t) Het in which t is 0, 1, 2, 3 or 4, and the alkylene chain isoptionally substituted by one or more C₁₋₃alkyl groups and Hetrepresents an aromatic heterocycle optionally substituted by one, two orthree groups selected from a C₁₋₅alkyl group, a C₁₋₅alkoxy group orhalo; or R¹ represents H and R² is as defined above; or R¹ and R²together with the nitrogen atom to which they are attached represent asaturated 5 to 8 membered heterocyclic group containing one nitrogen andoptionally one of the following: oxygen, sulphur or an additionalnitrogen; wherein the heterocyclic group is optionally substituted byone or more C₁₋₃alkyl groups, hydroxy or benzyl; X is CO or SO₂; Y isabsent or represents NH optionally substitututed by a C₁₋₃alkyl group;R³ and R⁴ independently represent phenyl, thienyl or pyridyl each ofwhich is optionally substituted by one, two or three groups representedby Z; Z represents a C₁₋₃alkyl group, a C₁₋₃alkoxy group, hydroxy, halo,trifluoromethyl, trifluoromethylthio, trifluoromethoxy,trifluoromethylsulphonyl, nitro, amino, mono or di C₁₋₃alkylamino, monoor di C₁₋₃alkylamido, C₁₋₃alkylsulphonyl, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkyl carbamoyl, sulphamoyl and acetyl;and R⁵ is H, a C₁₋₃alkyl group, a C₁₋₃alkoxymethyl group,trifluoromethyl, a hydroxyC₁₋₃alkyl group, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkylcarbamoyl, acetyl, orhydrazinocarbonyl of formula —CONHNR^(a)R^(b) wherein R^(a) and R^(b)are as previously defined for R¹ and R² respectively and; with theproviso that when R¹ and R² together with the nitrogen atom to whichthey are attached represent 4-methylpiperazin-1-yl or R¹ represents Hand R² represents methyl or 1-benzylpiperidin-4-yl; X is CO; Y is absentand R⁵ is H; then R³ and R⁴ do not both represent 4-methoxyphenyl.
 2. Acompound according to claim 1 in which R¹ represents H, R² representscyclohexyl, X is CO and Y is absent.
 3. A compound according to claim 1in which R¹ and R² together with the nitrogen atom to which they areattached represent 1-piperidinyl.
 4. A compound according to claim 1 inwhich R¹ represents H and R² represents phenyl.
 5. A compound accordingto claim 1 as represented by formula Ia

and pharmaceutically acceptable salts, solvates and crystalline formsthereof, in which R² represents cyclohexyl, 1-piperidinyl or phenyl; R⁶represents H, chloro, bromo, methyl or methoxy; and when R⁷ representsH, R⁸ represents H or chloro; and when R⁷ represents chloro, R⁸represents H or chloro.
 6. A compound according to any one of claims 1to 4 in which R⁵ is H.
 7. A compound according to any one of claims 1 to4 in which X is CO.
 8. A compound according to any one of claims 1 to 4in which X is SO₂.
 9. A compound according to any one of claims 1 to 4in which Y is absent.
 10. A compound selected from:N-(1-piperidinyl)-5,6-diphenyl-2-pyrazinecarboxamide;N-(1-piperidinyl)-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide;N-(1-piperidinyl)-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;N-(1-piperidinyl)-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;N-(1-piperidinyl)-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;N-(1-piperidinyl)-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;N-cyclohexyl-5,6-diphenyl-2-pyrazinecarboxamide;N-cyclohexyl-5,6-bis(4-bromophenyl)-2-pyrazinecarboxamide;N-cyclohexyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;N-cyclohexyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;N-cyclohexyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;N-cyclohexyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;N,5,6-triphenyl-2-pyrazinecarboxamide;N-phenyl-5,6-bis(4-methylphenyl)-2-pyrazinecarboxamide;N-phenyl-5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxamide;N-phenyl-5,6-bis(4-chlorophenyl)-2-pyrazinecarboxamide;N-phenyl-5,6-bis(2-chlorophenyl)-2-pyrazinecarboxamide;N-(1-piperidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-2-pyrazinecarboxamide;andN-(1-piperidinyl)-6-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-pyrazinecarboxamide;and where applicable, optical isomers, tautomers, stereoisomers andracemates thereof as well as pharmaceutically acceptable salts, solvatesand crystalline forms thereof.
 11. A compound of formula I as claimed inany previous claim for use as a medicament.
 12. A pharmaceuticalformulation comprising a compound of formula I, as defined in any one ofclaims 1 to 10 and a pharmaceutically acceptable adjuvant, diluent orcarrier.
 13. Use of a compound of formula I

and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof, in which R¹ and R² independently represent: aC₁₋₆alkyl group; an (amino)C₁₋₄alkyl-group in which the amino isoptionally substituted by one or more C₁₋₃alkyl groups; an optionallysubstituted non-aromatic C₃₋₁₅carbocyclic group; a(C₃₋₁₂cycloalkyl)C₁₋₃alkyl-group; a group —(CH₂)_(r)(phenyl)_(s) inwhich r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 andthe phenyl groups are optionally independently substituted by one, twoor three groups represented by Z; naphthyl; anthracenyl; a saturated 5to 8 membered heterocyclic group containing one nitrogen and optionallyone of the following: oxygen, sulphur or an additional nitrogen whereinthe heterocyclic group is optionally substituted by one or moreC₁₋₃alkyl groups, hydroxy or benzyl; 1-adamantylmethyl; a group—(CH₂)_(t) Het in which t is 0, 1, 2, 3 or 4, and the alkylene chain isoptionally substituted by one or more C₁₋₃alkyl groups and Hetrepresents an aromatic heterocycle optionally substituted by one, two orthree groups selected from a C₁₋₅alkyl group, a C₁₋₅alkoxy group orhalo; or R¹ represents H and R² is as defined above; or R¹ and R²together with the nitrogen atom to which they are attached represent asaturated 5 to 8 membered heterocyclic group containing one nitrogen andoptionally one of the following: oxygen, sulphur or an additionalnitrogen; wherein the heterocyclic group is optionally substituted byone or more C₁₋₃alkyl groups, hydroxy or benzyl; X is CO or SO₂; Y isabsent or represents NH optionally substitututed by a C₁₋₃alkyl group;R³ and R⁴ independently represent phenyl, thienyl or pyridyl each ofwhich is optionally substituted by one, two or three groups representedby Z; Z represents a C₁₋₃alkyl group, a C₁₋₃alkoxy group, hydroxy, halo,trifluoromethyl, trifluoromethylthio, trifluoromethoxy,trifluoromethylsulphonyl, nitro, amino, mono or di C₁₋₃alkylamino, monoor di C₁₋₃alkylamido, C₁₋₃alkylsulphonyl, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkyl carbamoyl, sulphamoyl and acetyl;and R⁵ is H, a C₁₋₃alkyl group, a C₁₋₃alkoxymethyl group,trifluoromethyl, a hydroxyC₁₋₃alkyl group, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkylcarbamoyl, acetyl, orhydrazinocarbonyl of formula —CONHNR^(a)R^(b) wherein R^(a) and R^(b)are as previously defined for R¹ and R² respectively; in the preparationof a medicament for the treatment or prophylaxis of obesity, psychiatricdisorders such as psychotic disorders, schizophrenia and bipolardisorders, anxiety, anxio-depressive disorders, depression, cognitivedisorders, memory disorders, obsessive-compulsive disorders, anorexia,bulimia, attention disorders, epilepsy, and related conditions, andneurological disorders such as dementia, neurological disorders,Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease,immune, cardiovascular, reproductive and endocrine disorders, septicshock, diseases related to the respiratory and gastrointestinal systems,and extended abuse, addiction and/or relapse indications.
 14. A methodof treating obesity, psychiatric disorders, psychotic disorders,schizophrenia and bipolar disorders, anxiety, anxio-depressivedisorders, depression, cognitive disorders, memory disorders,obsessive-compulsive disorders, anorexia, bulimia, attention disorders,epilepsy, and related conditions, neurological disorders, neurologicaldisorders, Parkinson's Disease, Huntington's Chorea and Alzheimer'sDisease, immune, cardiovascular, reproductive and endocrine disorders,septic shock, diseases related to the respiratory and gastrointestinalsystem, and extended abuse, addiction and/or relapse indications,comprising administering a pharmacologically effective amount of acompound of formula I

and pharmaceutically acceptable salts, prodrugs, solvates andcrystalline forms thereof, in which R¹ and R² independently represent: aC₁₋₆alkyl group; an (amino)C₁₋₄alkyl-group in which the amino isoptionally substituted by one or more C₁₋₃alkyl groups; an optionallysubstituted non-aromatic C₃₋₁₅carbocyclic group; a(C₃₋₁₂cycloalkyl)C₁₋₃alkyl-group; a group —(CH₂)_(r)(phenyl)_(s) inwhich r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 andthe phenyl groups are optionally independently substituted by one, twoor three groups represented by Z; naphthyl; anthracenyl; a saturated 5to 8 membered heterocyclic group containing one nitrogen and optionallyone of the following: oxygen, sulphur or an additional nitrogen whereinthe heterocyclic group is optionally substituted by one or moreC₁₋₃alkyl groups, hydroxy or benzyl; 1-adamantylmethyl; a group—(CH₂)_(t) Het in which t is 0, 1, 2, 3 or 4, and the alkylene chain isoptionally substituted by one or more C₁₋₃alkyl groups and Hetrepresents an aromatic heterocycle optionally substituted by one, two orthree groups selected from a C₁₋₅alkyl group, a C₁₋₅alkoxy group orhalo; or R¹ represents H and R² is as defined above; or R¹ and R²together with the nitrogen atom to which they are attached represent asaturated 5 to 8 membered heterocyclic group containing one nitrogen andoptionally one of the following: oxygen, sulphur or an additionalnitrogen; wherein the heterocyclic group is optionally substituted byone or more C₁₋₃alkyl groups, hydroxy or benzyl; X is CO or SO₂; Y isabsent or represents NH optionally substitututed by a C₁₋₃alkyl group;R³ and R⁴ independently represent phenyl, thienyl or pyridyl each ofwhich is optionally substituted by one, two or three groups representedby Z; Z represents a C₁₋₃alkyl group, a C₁₋₃alkoxy group, hydroxy, halo,trifluoromethyl, trifluoromethylthio, trifluoromethoxy,trifluoromethylsulphonyl, nitro, amino, mono or di C₁₋₃alkylamino, monoor di C₁₋₃alkylamido, C₁₋₃alkylsulphonyl, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkyl carbamoyl, sulphamoyl and acetyl;and R⁵ is H, a C₁₋₃alkyl group, a C₁₋₃alkoxymethyl group,trifluoromethyl, a hydroxyC₁₋₃alkyl group, C₁₋₃alkoxycarbonyl, carboxy,cyano, carbamoyl, mono or di C₁₋₃alkylcarbamoyl, acetyl, orhydrazinocarbonyl of formula —CONHNR^(a)R^(b) wherein R^(a) and R^(b)are as previously defined for R¹ and R² respectively; to a patient inneed thereof.
 15. A compound as defined in any one of claims 1 to 10 foruse in the treatment of obesity.
 16. A process for the preparation of acompound of formula I comprising a) reacting a compound of formula II

in which R³, R⁴ and R⁵ are as previously defined with an amine offormula IIIR¹R²YNH₂  III in an inert solvent in the presence of a coupling agentand optionally in the presence of a catalyst at a temperature in therange of −25° C. to 150° C. to give a compound of formula I in which Xis CO; or b) reacting a compound of formula IV

in which R³, R⁴ and R⁵ are as previously defined and A represents halowith an amine of formula VR¹R²YNH₂  V in an inert solvent and optionally in the presence of acatalyst at a temperature in the range of −25° C. to 150° C. to give acompound of formula I in which X is SO₂.
 17. A compound of formula II

in which R³, R⁴ and R⁵ are as previously defined with the exception of5,6-diphenyl-2-pyrazinecarboxylic acid and5,6-bis(4-methoxyphenyl)-2-pyrazinecarboxylic acid.